1.A.9.3.1Adult strychnine-sensitive glycine-inhibited chloride (anion selective) heteropentameric channel (GlyR; GLRA1) consisting of α1- and β-subunits (Cascio, 2004; Sivilotti, 2010). Ivermectin potentiates glycine-induced channel activation (Wang and Lynch, 2012). Molecular sites for the positive allosteric modulation of glycine receptors by endocannabinoids have been identified (Yévenes and Zeilhofer, 2011). Different subunits contribute asymmetrically to channel conductances via residues in the extracellular domain (Moroni et al., 2011; Xiong et al., 2012). Dominant and recessive mutations in GLRA1 are the major causes of hyperekplexia or startle disease (Gimenez et al., 2012). Open channel 3-d structures are known (Mowrey et al. 2013). Desensitization is
regulated by interactions between the second and third transmembrane segments which affect the ion
channel lumen near its intracellular end. The GABAAR and GlyR pore blocker, picrotoxin (TC# 8.C.1), prevents
desensitization (Gielen et al. 2015). The x-ray structure of the α1 GlyR transmembrane domain has been reported (Moraga-Cid et al. 2015), and residue S296 in hGlyR-alpha1
is involved in potentiation by Delta(9)-tetrahydrocannabinol (THC) (Wells et al. 2015). The structure has also been elucidated by cryo EM (Du et al. 2015) and by x-ray crystalography (Huang et al. 2015). The latter presented a 3.0 A X-ray structure of the human glycine receptor-alpha3 homopentamer in complex with the
high affinity, high-specificity antagonist, strychnine. The structure allowed exploration of
the molecular recognition of antagonists. Comparisons with previous structures revealed a mechanism
for antagonist-induced inactivation of Cys-loop receptors, involving an expansion of the orthosteric
binding site in the extracellular domain that is coupled to closure of the ion pore in the
transmembrane domain. The GlyR beta8-beta9 loop is an essential regulator of conformational rearrangements during ion channel opening and closing (Schaefer et al. 2017). Association of GlyR with the anchoring protein, gephyrin (Q9NQX3), is due to a hydrophobic interaction formed by Phe 330 of gephyrin and Phe 398 and Ile 400 of the GlyR beta-loop (Kim et al. 2006). Alcohols and volatile anesthetics enhance the function of inhibitory glycine receptors (GlyRs) by binding to a single anaesthetic binding site (Roberts et al. 2006). Aromatic residues in the GlyR M1, M3 and M4 α-helices are essential for receptor function (Tang and Lummis 2018). The neurological disorder, startle disease, is caused by glycinergic dysfunction, mainly due to missense mutations in genes encoding GlyR subunits (GLRA1 and GLRB). Another neurological disease with a phenotype similar to startle disease is a special form of stiff-person syndrome (SPS), which is most probably due to the development of GlyR autoantibodies (Schaefer et al. 2018). GlyRs can be modulated by positive allosteric modulators (PAMs) that target the extracellular, transmembrane and intracellular domains (Lara et al. 2019). Mutations in GLRA1 give rise to hyperekplexia (Milenkovic et al. 2018). Neurosteroid binding sites of GABAARs are conserved in the GlyRs (Alvarez and Pecci 2019). The intracellular domain of homomeric glycine receptors modulates agonist efficacy (Ivica et al. 2020). Inhibitory glycinergic transmission in the adult spinal cord is primarily mediated by glycine receptors
(GlyRs) containing the alpha1 subunit. Alpha1ins, a longer alpha1
variant with 8 amino acids inserted into the intracellular large loop
between TMSs 3 and 4, is expressed in the dorsal horn of the spinal
cord, distributed at inhibitory synapses, and it is engaged in negative
control over nociceptive signal transduction. Activation of metabotropic
glutamate receptor 5 (mGluR5; TC# 9.A.14.7.1) specifically suppressed
alpha1ins-mediated glycinergic transmission and evoked pain
sensitization. Extracellular signal-regulated kinase (ERK) was critical
for mGluR5 to inhibit alpha1ins. By binding to a D-docking site created
by the 8-amino-acid insert ERK catalyzed alpha1ins phosphorylation at
Ser380, which favored alpha1ins ubiquitination at Lys379 and led to
alpha1ins endocytosis. Disruption of the ERK interaction with alpha1ins
blocked Ser380 phosphorylation, potentiated glycinergic synaptic
currents, and alleviated inflammatory and neuropathic pain (Zhang et al. 2019).